Navigating challenges and opportunities in orphan medicines: A spotlight commentary on rare diseases

1. INTRODUCTION

Rare diseases, defined as those affecting fewer than 200 000 individuals in the United States and fewer than 5 in 10 000 in the EU, collectively impact approximately 300 million people globally. ¹ Patients with rare diseases have always been a marginalized group, particularly in low‐ and middle‐income countries due to lack of effective treatment and accurate diagnostic methods and insufficient knowledge of health professionals. Following incentives by national governments globally, significant advances have been made during the last decades towards the development of medicines for orphan diseases. However, there are still significant challenges to address, mainly pertaining to the design of clinical trials and the significant costs associated with orphan medicines, both at the R&D level and at the access level. Apart from the medical and economic burden associated with rare diseases, the psychological burden they pose to the patients is profound. ² The spotlight commentary at hand will reference both regulatory and real‐world insights, drawn from existing literature. ³ The British Journal of Clinical Pharmacology has taken a keen interest in the challenges around the development of orphan medicines in rare diseases and has charted the progress made in the field over the decades; thus, the journal's website was searched for references using the keywords ‘rare disease’ and ‘orphan drug/medicine’.

As Joppi et al. reported in the British Journal of Clinical Pharmacology 15 years ago, due to the small patient population associated with each rare disease, pharmaceutical companies did not see a commercial interest in this market. ⁴ That said, thanks to incentives provided by national governments and the European Union (EU), the situation has significantly improved during the last decades. Furthermore, recruiting patients with rare diseases into clinical trials can be challenging, both due to the small population and geographical hurdles, thus compromising the trial design and the robustness of the results, especially when it comes to ultra rare diseases. When the data reported in clinical trials are not seen as robust, this can lead to regulatory delays. Real‐world evidence (RWE) studies can play an important role in addressing this significant issue, as Polak et al. report in the British Journal of Clinical Pharmacology. ⁵ RWE, which can take many forms including observational studies, natural history studies, electronic health records and claims databases, bears the grate advantage of a much less complicated and quicker process of data collection, contrary to clinical trials. ⁶ RWE data have not traditionally been considered during regulatory processes by national authorities; however, positive progress has been made recently in this aspect, with both the US Food and Drug Administration and the European Medicines Agency including RWE data in their regulatory approval reports. ⁷ Another issue inherent in orphan medicines' research is their associated safety, given the potential heterogeneity in the genetic profiling of the patient population. Prospective, post‐marketing surveillance studies are of the utmost importance in this aspect, ensuring the long‐term safety and clinical benefit of the products, as analysed by Dupont et al. in the British Journal of Clinical Pharmacology. ⁸ Despite the challenges, there has been significant progress in this setting, with genetic profiling being a catalyst towards the tailoring of treatments for patients with rare diseases. ⁹

Diagnosing rare diseases can be transformed by the introduction of metabolomics, proteomics and methyl profiling, as well as complementing short‐read genome sequencing with RNA sequencing. These methods are increasingly important in standard of care and clinical trials for rare diseases, as seen, for instance, in lysosomal storage disease genotype–phenotype correlations, which are an intrinsic part of clinical trial designs. That said, such methods are significantly expensive, posing a challenge for the accurate and timely diagnosis of patients. Lastly, gene therapies represent a transformative approach in the field, as a significant proportion of patients have a monogenic disease. While these therapies offer significant potential benefits, they are associated with unique challenges that impact patient access and treatment efficacy. ¹⁰

Orphan medicines are associated with high costs linked with the development of medicinal products, as well as with a lower market volume that consequently drives a lower return on investment. In a systematic review of pharmacoeconomic evaluations for orphan medicines for the treatment of spinal muscular atrophy, Belančić et al. found that the medicines were found not cost‐effective in multiple studies. ¹¹ While orphan medicines can deliver significant health gains, they are rarely found to be cost‐effective; this poses the question whether benchmarks, that is, willingness‐to‐pay (WTP) thresholds, are the optimal choice when appraising medicines for rare diseases. The notion that different payer models may be needed to address the challenge of cost‐effectiveness has become more popular in both academic and policy settings, with national authorities, such as the United Kingdom and Germany, having set WTP thresholds specific for orphan medicines, to ensure their timely reimbursement and market access. The reimbursement of orphan medicines is critical in guaranteeing patient access. If a medicine is not reimbursed by either the public or private sector, patients are asked to cover significant out‐of‐pocket costs, which leads to patients being excluded from receiving appropriate treatment due to insufficient funds, particularly in low‐ and middle‐income countries, thus increasing the already existing health inequities this patient group faces. In the EU, the countries where the most orphan medicines are available on the market are Italy, the Netherlands, France and Belgium. ⁴ , ⁸ Notably, reimbursement policies and WTP thresholds vary significantly and historically between countries, influenced by different national policies, economic conditions and so forth, while there is no ‘gold standard’ method when appraising the cost‐effectiveness of medicines. In the United States, a WTP threshold ranging between $50 000 and $100 000 has been set and is still used since 1982, jeopardizing the reimbursement of orphan medicines and consequently, patient access. Even in countries with universal healthcare, such as Sweden, an explicit WTP threshold for orphan medicines has not been set, proving that there is a long road ahead when it comes to the reimbursement of orphan medicines. ¹¹

A range of different approaches to research around orphan medicines have been pursued, with the repurposing of existing medicines being the first choice and a potential opportunity to render orphan medicines affordable, as analysed by Mifsud et al. ¹² Research has shown that the same orphan medicine might be an effective treatment option for several, even unrelated, rare diseases. For example, colchicine, a drug that was initially indicated for gouty arthritis, has proved to be effective in patients with familial Mediterranean fever. While repurposing existing medicines offers a faster, more cost‐effective way to address rare diseases, there are patients who are resistant to this type of treatment, so research for alternative therapies is required. Another factor that acted as a catalyst for the development of orphan medicines is the adoption of innovative regulatory pathways by the FDA, the EMA and so forth, in the form of fast‐track appraisals and adaptive clinical trials, which played an important role in speeding up the patient access to life‐saving treatments. ¹³ Furthermore, the importance of multifactorial partnerships and collaboration including national governments, patient organizations, the industry and the academic community should not be overlooked. It is with this collaboration that progress has been made until this day, and it should be reinforced further to overcome the hurdles pertaining to orphan medicines.

As aforementioned, rare diseases were initially neglected by both public policy and industry, with the former believing rare diseases affected a very narrow part of the population and the latter thinking that the cost of developing therapies would outweigh the benefits. A shift in paradigm came in 1983, when the US government implemented the Orphan Drug Act, which provided the pharmaceutical companies with incentives to start developing orphan medicines. ⁸ Similar legislations were adopted by Japan, Australia and Singapore in 1985, 1990 and 1991, respectively, as was well summarized by the current editor‐in‐chief of the British Journal of Clinical Pharmacology. ¹⁴ The EU also adopted such policy in 2000, with the Regulation on Orphan Medicinal Products. Without these incentives, it was deemed unlikely that the expected sales of the orphan medicines would exceed the cost of their development. The pharmaceutical industry responded to these incentives, as evidenced by the increased number of orphan medicine designations and approvals since 2000 in the EU. In May 2024, the FDA's Center for Biologics Evaluation and Research (CBER) launched the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot programme, which is designed to facilitate communication between sponsors of rare disease therapies and FDA officials, providing guidance on various aspects of clinical trial design and regulatory processes. This includes advice on clinical study design, control group selection, patient population targeting and product characterization. ¹⁵ Moreover, the Rare Disease Endpoint Advancement (RDEA) Pilot Programme is another initiative by the FDA aimed at improving the development of therapies for rare diseases. This programme focuses on establishing and validating endpoints that can be used in clinical trials for rare diseases, which often lack established measures for assessing treatment efficacy. ¹⁶

A comprehensive image of the trends in orphan medicines and rare diseases research and regulatory outcomes is shown in Figure 1. As aforementioned, despite the recent advances, orphan medicines continue to be expensive, and their reimbursement can negatively impact the budget of healthcare systems. This in turn begs the question of resource allocation and specifically how to find the right balance between funding orphan medicines and not sacrificing other health services that affect the general population. ¹⁷ Moreover, the role of patient organizations cannot be downplayed when it comes to rare diseases; their advocacy was paramount in pushing for research for orphan medicines, and their role is only growing, thanks to online communities and some overarching patient organizations, such as the US National Organization for Rare Diseases, as reported by Cremers et al. ¹⁴ The work of these organizations is pivotal in encouraging decision‐makers to adopt patient‐centred approaches, offering hope for overcoming significant challenges in this field.

FIGURE 1.

Trends in orphan medicines and rare diseases research and regulatory outcomes (2000–2023); (A) number of PubMed articles (2000–2023) related to orphan medicine; (B) number of PubMed articles (2000–2023) related to rare diseases; (C) orphan medicinal product designation overview (2000–2023), detailing submissions, positive COMP opinions, EC designations, refusals and withdrawals; (D) COMP opinions from 2023 stratified by MeDRA classification categories.COMP, Committee for Orphan Medicinal Products; EC, European Commission; MeDRA, Medical Dictionary for Regulatory Activities.

In conclusion, although there remains significant progress to be made in the development of orphan medicines, the recent advances are commendable, as they have led to tangible improvements in patient care and quality of life. The public health challenges posed by rare diseases have prompted a paradigm shift, particularly in the incorporation of RWE in the approval process for orphan drugs. Nonetheless, further efforts are needed to address the economic challenges, specifically in making these medicines more affordable and cost‐effective. The strides made so far have been possible through the collaborative efforts of national authorities, industry stakeholders, patient advocacy groups and international organizations. Strengthening this multifaceted partnership is crucial for overcoming existing barriers and ensuring that patients with rare diseases continue to gain access to safe and effective treatments.

Thus, ultimate aim of this BJCP spotlight commentary is to encourage rare disease specialists and other stakeholders to team up with clinical pharmacologists, think about meaningful endpoints and start/continue collecting top quality data. ¹⁸

AUTHOR CONTRIBUTIONS

Conceptualization: Andrej Belančić. Investigation: Andrej Belančić and Elvira Meni Maria Gkrinia. Project administration: Andrej Belančić. Supervision: Dinko Vitezić and Robert Likić. Writing—original draft: Andrej Belančića and Elvira Meni Maria Gkrinia. Writing—review and editing: Andrej Belančić, Elvira Meni Maria Gkrinia, Robert Likić and Dinko Vitezić.

All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Belančić A, Gkrinia EMM, Likić R, Vitezić D. Navigating challenges and opportunities in orphan medicines: A spotlight commentary on rare diseases. Br J Clin Pharmacol. 2025;91(4):1084‐1087. doi: 10.1002/bcp.70013

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article.